Particulate preparations having drugs enclosed in fine particles called nanoparticle, microparticle, nanosphere, microsphere, or microcapsule are developed, and are attempted to be used as sustained-release agents for drugs.
Particulate preparations using polymer compounds as the base include fine particles composed of biodegradable polylactic acid or poly(lactic acid-glycolic acid). In these particulate preparations, it is hard to encapsulate a protein or a peptide drug of hydrophilic property and large molecular weight while maintaining the bioactivity. In addition, when administering in the human body, it is known that the drug is massively released in a short time, and this phenomenon is called an initial burst.
As fine particles composed of a polymer of covalent bonding of saccharide and poly(hydroxy acid), JP 8-19226 discloses a microcapsule for carrying a pharmacologically active substance composed of a reaction product of polyol and polylactic acid. In this technique, polysaccharides are not used, and nothing is mentioned about inclusion of peptide or protein. The microcapsule manufactured by a spray drying method released the encapsulated drug by 62% in 24 hours. This release speed is too fast, and the microcapsule can be hardly applied as a sustained-release agent for a drug.
JP 2004-521152 and Yuichi Ohya et al., “Encapsulation and/or Release Behavior of Bovine Serum Albumin within and from Polylactide-Grafted Dextran Microsphers,” Macromolecular Bioscience, 2004, Vol. 4, pp. 458-463 disclose a nanoparticle or a nanoparticle composed of a material having a biodegradable polymer grafted in polysaccharides, but these literatures mention nothing about a microparticle composed of nanoparticles. JP 2004-521152 discloses, for example, a double emulsion method already cited in other literatures, as a manufacturing method of a microparticle for encapsulating a hydrophilic active substance, but there is no specific description, and inclusion of a drug into a particle, or release of a drug from a particle is not realized. Yuichi Ohya et al., “Encapsulation and/or Release Behavior of Bovine Serum Albumin within and from Polylactide-Grafted Dextran Microsphers,” Macromolecular Bioscience, 2004, Vol. 4, pp. 458-463 discloses a microparticle encapsulating an albumin manufactured by the double emulsion method, but the encapsulation efficiency to the included amount of the albumin is 53% or less, and the low encapsulation efficiency of the hydrophilic active substance has a problem in the manufacturing cost.
WO 2006/095668 discloses a fine particle containing an amphiphilic polymer composed of polysaccharides and an aliphatic polyester, more specifically a fine particle composed of an inner nucleus of polysaccharides, a hydrophobic outer layer of aliphatic polyester, and a surface modifier bonded to the hydrophobic outer layer. This fine particle does not have an agglomeration structure of fine particles, and specific examples are not shown about particles of particle diameter of micrometer units. The encapsulation efficiency of the hydrophilic substance is 50% or less, and this low encapsulation efficiency is a similar problem as in the case above.
JP 10-511957 discloses a nanoparticle of average particle diameter of less than 300 nm, composed of a naturally derived polymer of dextran, but specific examples are not shown. This is not an agglomeration structure of fine particles, and the average particle diameter is hundreds of nanometers, and the drug is likely to diffuse from the site of administration, and it is not preferred as a sustained-release agent.
As the polymer for forming particles, JP 2004-513154 and JP 2004-514734 disclose and suggest use of an amphiphilic block polymer having a hydrophilic portion such as polyethylene glycol, and a hydrophobic portion such as poly(lactic acid-glycolic acid). Micelle particles using such amphiphilic block polymer are usually hydrophobic in the inside, and hydrophilic in the outer layer, and they are suited to containment of hydrophobic low molecular weight drugs, but not suited to containment of hydrophilic active substances such as protein or peptide.
JP 2000-501084 and Anshu Yang et al., “Tumor necrosis factor alpha blocking peptide loaded PEG-PLGA nanopeptides: Preferparation and in vitro evaluation,” International Journal of Pharmaceutics, 2007, Vol. 331, pp. 123-132 disclose attempts to contain a protein in a particle using an amphiphilic block polymer, but the amount of the drug to be contained is small, or the initial burst is large, and so far the manufacturing technology of particles having properties suited as sustained-release injection of a hydrophilic drug is not established yet.
As mentioned above, microparticles using a polymer have been developed. Hence, it could be helpful to provide a microparticle capable of encapsulating a hydrophilic active substance efficiently, and more particularly a microparticle capable of releasing the encapsulated drug at an appropriate speed, without causing significant initial burst.